EP1121351A4 - Preparation d'ester methylique d'acide (s)-2-amino-6,6-dimethoxyhexanoique - Google Patents

Preparation d'ester methylique d'acide (s)-2-amino-6,6-dimethoxyhexanoique

Info

Publication number
EP1121351A4
EP1121351A4 EP99932163A EP99932163A EP1121351A4 EP 1121351 A4 EP1121351 A4 EP 1121351A4 EP 99932163 A EP99932163 A EP 99932163A EP 99932163 A EP99932163 A EP 99932163A EP 1121351 A4 EP1121351 A4 EP 1121351A4
Authority
EP
European Patent Office
Prior art keywords
formula
compound
amino
acid
methyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99932163A
Other languages
German (de)
English (en)
Other versions
EP1121351A2 (fr
Inventor
Jollie D Godfrey Jr
David R Kronenthal
Mark D Schwinden
Sushil K Srivastava
Keith Ramig
John J Venit
Paul A Jass
Saibaba Racha
John L Dillon Jr
Nachimuthu Soundararajan
Gerald L Powers
Atul S Kotnis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of EP1121351A2 publication Critical patent/EP1121351A2/fr
Publication of EP1121351A4 publication Critical patent/EP1121351A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • X can be S
  • Y can be CH2
  • m can be one
  • n can be two as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity.
  • X can be S
  • Y can be CH2
  • m can be one
  • n can be two as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity.
  • Among these compounds is [4S- [4 ⁇ (R*) ,7 , lOa ⁇ ] ] -octahydro-4- [ (2-mercapto-l-oxo-3- phenylpropyl-amino] -5-oxo-7H-pyrido [2 , 1-b] [1,3] thiazepine- 7-carboxylic acid which is currently undergoing clinical evaluation.
  • This compound is reported in the literature as BMS 186,716 and as omapatrilat.
  • This invention is directed to an improved chemical synthesis of (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester and novel dioxolane intermediates from this synthesis.
  • L is a leaving group such as iodo, bromo, alkylsulfonyloxy, or arylsulfonyloxy to give the dioxolane of the formula (III)
  • the dioxolane of formula III is treated under aqueous refluxing conditions to give the dioxolane pentanoic acid of the formula
  • the dioxolane pentanoic acid of formula IV is then treated to exchange the dioxolane acetal with a dimethoxy acetal and convert the carboxylic acid to the methyl ester resulting in the desired compound (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester.
  • Another aspect of this invention is the preparation of storage stable salts of (S) -2-amino-6 , 6- dimethoxyhexanoic acid, methyl ester of formula X.
  • Such salts can be converted to the free amine for ultimate conversion to the desired product. This affords added flexibility in scheduling production runs and enables different stages of the reaction to be carried out at different manufacturing facilities.
  • (S)-2- amino-6, 6-dimethoxyhexanoic acid, methyl ester of formula X is prepared by a chemical synthesis that avoids the need for an oxidation reaction and for an optical resolution.
  • the glycinamide of formula I is reacted with the dioxolane of formula II to give the dioxolane of formula III.
  • This reaction is performed in the presence of lithium diisopropylamide in an organic solvent such as tetrahydrofuran, which is preferred, diethoxymethane, tert- butyl methyl ether, 2-methyl tetrahydrofuran, or diethyl ether.
  • the reaction is carried out at a temperature of from about -78°C to about 0°C.
  • the glycinamide of formula I is prepared as described by Myers et al . , Tetrahedron Letters , Vol. 36, p. 4555 - 4558 (1995) .
  • the leaving group L in the dioxolane reagent of formula II can be an alkylsulfonyloxy such as methane sulfonyloxy, an arylsulfonyloxy such as p-toluenesulfonyloxy, bromo, or iodo with iodo being preferred.
  • Such dioxolane reagents of formula II are known in the art or can be prepared from commercially available compounds.
  • the dioxolane of formula II wherein L is iodo can be prepared by reacting 2- (3-chloropropyl) -1 , 3-dioxolane with sodium iodide in the presence of sodium bicarbonate.
  • the dioxolane intermediate of formula III is then treated under aqueous refluxing conditions to give the dioxolane pentanoic acid of formula IV.
  • the dioxolane pentanoic acid of formula IV is then reacted to give (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester of formula X by exchanging the dioxolane acetal with a dimethoxy acetal and introducing the methyl ester group.
  • the dioxolane pentanoic acid of formula IV can be reacted with thionyl chloride in methanol or reacted with anhydrous HCl such as HCl gas and dimethyl sulfite in methanol or reacted with HCl generated in si tu such as by reacting the compound of formula IV with chlorotrimethylsilane or an acid chloride such as acetyl chloride and dimethyl sulfite in methanol to give the desired compound of formula X.
  • These reactions can be performed at a temperature of from about 40°C to about 45°C.
  • (S) -2-Amino-6, 6-dimethoxyhexanoic acid, methyl ester can be converted to a storage stable salt. This provides added flexibility to the overall process as the process steps leading up to the (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester salt can be performed separately from the process steps for converting (S) -2-amino-6 , 6- dimethoxyhexanoic acid, methyl ester to the desired final product.
  • storage stable salt refers to a salt of (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester which can be maintained for a period of at least about 30 days under conditions of low temperature and the absence of moisture and then converted to (S) -2-amino-6 , 6-dimethoxy- hexanoic acid, methyl ester in high yields.
  • (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester of formula X suitable for this purpose include the oxalic acid salts (1:1) and (2:1), the diphenylacetic acid salt (1:1), and the phosphoric acid salt (1:1) .
  • the salt is treated with a base such as potassium bicarbonate to give the (S) -2-amino-6 , 6-dimethoxyhexanoic acid, methyl ester of formula X.
  • a base such as potassium bicarbonate
  • (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester of formula X can be coupled with the N-protected amino acid of the formula (V)
  • Pi is an amino protecting group such as benzyloxycarbonyl or t-butoxycarbonyl or a group which together with the N-atom forms a protecting group such as phthalimido and P2 is a mercapto protecting group such as acetyl or benzoyl .
  • This coupling reaction is preferably performed in the presence of a coupling reagent such as benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate, ethyl-3- (3-dimethylamino)propyl carbodiimide, methanesulfonyloxybenzotriazole, or dicyclohexylcarbodiimide.
  • the P2 protecting group is selectively removed from the dipeptide of formula VI such as by treatment with sodium methoxide in methanol or by treatment with p-toluenesulfonic acid in methanol.
  • the resulting mercaptan compound is then subjected to an acid catalyzed cyclization reaction preferably by treating with a strong acid such as trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or a commercially available polystyrene sulfonate polymer type ion exchange resin such as Amberlystl5®.
  • This cyclization reaction can be performed in a non-protic solvent such as methylene chloride or chloroform to give the lactam of the formula (VII)
  • the lactam of formula VII is then treated to remove the Pi N-protecting group and then reacted with the acylmercaptoalkanoyl sidechain of the formula (VIII)
  • R ⁇ is methyl or phenyl giving the compound of the formula
  • This coupling reaction can be performed in an organic solvent such as methylene chloride and in the presence of a coupling reagent such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, benzotriazol-1-yloxytris- (dimethy1amino) phosphonium hexafluorophosphate, carbonyldiimidazole, or 1-propanephosphoric acid, cyclic anhydride.
  • a coupling reagent such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, benzotriazol-1-yloxytris- (dimethy1amino) phosphonium hexafluorophosphate, carbonyldiimidazole, or 1-propanephosphoric acid, cyclic anhydride.
  • the Pi N-protecting group can be removed from the lactam of formula VII, for example, by treatment with hydrazine monohydrate when Pi together with the N-atom forms a phthalimido group or by treatment with iodotrimethylsilane or palladium on carbon and hydrogen when Pi is benzyloxycarbonyl or by treatment with hydrochloric acid in dioxane or other strong acid when Pi is t-butoxycarbonyl .
  • the compound of formula IX is treated to remove the acyl group R 6 -C(0)- and to convert the methyl ester to the carboxylic acid as shown in the desired final product of formula XI.
  • R6 is methyl
  • treatment with methanolic sodium hydroxide followed by aqueous acid yields the desired compound of formula XI.
  • thiazepine-7-carboxylic acid possesses angiotensin converting enzyme and neutral endopeptidase inhibitory activity.
  • This compound as well as its pharmaceutically acceptable salts are useful in treating cardiovascular diseases such as hypertension and congestive heart failure as note Robl U.S. Patent 5,508,272.
  • This compound can be administered to a mammalian host such as man at from about 0.1 mg to about 100 mg per kg of body weight per day, preferably from about 0.5 mg to about 25 mg per kg of body weight per day.
  • the compound is preferably administered orally but parenteral routes and topical routes can also be employed.
  • the daily dose can be administered singly or can be divided into two to four doses administered throughout the day.
  • the following examples are illustrative of the invention.
  • a 0.5 liter, 4-necked, round-bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel and a nitrogen inlet/outlet was charged with 11.4 g of lithium chloride (dried in vacuo at 130°C for 6 hours and then at 100°C for 18 hours prior to use), 9.1 g of diisoproylamine and 80 ml of tetrahydrofuran. After cooling to -78°C, a 2.5 M solution of n-butyllithium in hexanes (35 ml) was added over about 20 minutes while maintaining the temperature at less than or equal to -60°C. This mixture was allowed to stir at -78°C for 45 minutes.
  • 2- (3-iodopropyl) -1, 3-dioxolane (12g) from part (a) was added as a tetrahydrofuran (10 ml) solution in one portion.
  • TLC analysis indicated no observable starting material present and water (100 ml) was added as a quench.
  • the tetrahydrofuran/hexane phase was separated from the lower aqueous phase .
  • the aqueous phase was extracted with methylene chloride (4 x 100 ml) .
  • the methylene chloride phases were combined with the tetrahydrofuran/hexane phase and washed with 100 ml of brine.
  • Example 2 The product of Example 2 was also prepared according to the following procedure.
  • Example 4 The product of Example 4 was also prepared according to the following procedure.
  • chlorotrimethyl silane (28.0 g) was added to a slurry of (S) - ⁇ -amino-1, 3-dioxolane-2-pentanoic acid (20.9 g) and dimethyl sulfite (12.0 g) in methanol (240 ml) to afford a homogeneous solution.
  • the solution was heated to 40-45°C, stirred at that temperature for 8 hours and at about 22°C for up to 72 hours.
  • In-process HPLC analysis showed that the reaction was complete (about 93 M% conversion to product) and the resulting solution was cooled to -5 to -10°C.
  • the batch volume was adjusted to about 400 ml with ethyl acetate and the resulting slurry was filtered.
  • Poly (acrylic acid co-acrylamide) , potassium salt (3.0 to 3.2 g) and water (30 - 32 ml) were added to the filtrate. The mixture was stirred for about 35 minutes and filtered.
  • the poly (acrylic acid co-acrylamide) , potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, 17.4 g of the title product was obtained as an ethyl acetate solution in 80.8 M% yield.
  • Potassium bicarbonate (104.3 g) was slurried in methanol (200 ml) contained in a 2-liter three neck flask and the reaction mixture containing the hydrochloride salt of (S) -2-amino-6, 6-dimethoxyhexanoic acid, methyl ester was neutralized by adding it to the potassium bicarbonate slurry while maintaining the pH of the mixture above 7.
  • HyFlo® (12.5 g) and n-butyl acetate (400 ml) were added and the mixture was concentrated under vacuum (76 to 180 mm of Hg) to remove methanol while maintaining the temperature of the mixture below 30°C.
  • tert-Butyl methyl ether 300 ml was added to the slurry and after cooling to -5°C, the salts of neutralization were removed by filtration and the filter cake was washed with tert-butyl methyl ether (50 ml) .
  • the combined filtrates were warmed to 20 to 25°C and a warm (approximately 27°C) methanolic (73 ml) solution of oxalic acid dihydrate (36.7 g) was added portionwise over about 1 hour.
  • the HPLC response was found to be linear in the range of 0.16 to 1.5 mg/ml . Samples were diluted with methanol or mobile phase.
  • Potassium bicarbonate (208.6 g) was slurried in methanol (400 ml) contained in a 5 liter three neck flask and the reaction containing the hydrochloride salt of (S) -2-amino-6 , 6- dimethoxyhexanoic acid, methyl ester was neutralized by adding it to the potassium bicarbonate slurry slowly over 1.5 hours while maintaining the pH of the mixture above 6.9.
  • the solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mm Hg and 30 to 40°C) maintaining a pot volume of about 2 liters.
  • Diphenylacetic acid (6.48 g) was dissolved, under nitrogen, in ethyl acetate (173 ml) at ambient temperature.
  • An ethyl acetate/tert-butyl methyl ether (1:2) (185 ml) solution of (S) -2-amino-6 , 6-dimethoxyhexanoic acid, methyl ester (6.27 g) was added to the diphenylacetic acid solution over 1 hour with stirring. Crystals of the salt precipitated immediately and the resulting thick slurry was diluted with tert-butyl methyl ether (100 ml) after about 65 ml of the aminoester solution had been added.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

L'invention concerne un glycinamide de formule (I) que l'on fait réagir avec le dioxolanne de formule (II), dans laquelle L désigne un groupe partant tel qu'un iode, bromo, alyklsulfonyloxy ou arylsulfonyloxy afin d'obtenir le dioxolanne de formule (III). L'invention concerne un procédé de traitement du dioxolanne de formule (III) dans des conditions aqueuses de reflux consistant à échanger le dioxolanne acétal avec un diméthoxy acétal et à introduire l'ester méthylique pour obtenir un ester méthylique d'acide (S)-2-amino-6,6-diméthoxyhexanoïque qui est un intermédiaire dans la préparation du double inhibiteur d'acide [4S-[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phénylpropy)-amino]-5-xo-7H-pyrido[2,1-b][1,3]thiazépine-7-carboxylique. Font aussi l'objet de cette invention des sels stables de stockage d'ester méthylique d'acide (S)-2-amino-6,6-diméthoxyhexanoïque.
EP99932163A 1998-07-15 1999-07-01 Preparation d'ester methylique d'acide (s)-2-amino-6,6-dimethoxyhexanoique Withdrawn EP1121351A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9294498P 1998-07-15 1998-07-15
US92944P 1998-07-15
PCT/US1999/014957 WO2000003981A2 (fr) 1998-07-15 1999-07-01 Preparation d'ester methylique d'acide (s)-2-amino-6,6-dimethoxyhexanoique

Publications (2)

Publication Number Publication Date
EP1121351A2 EP1121351A2 (fr) 2001-08-08
EP1121351A4 true EP1121351A4 (fr) 2003-05-02

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ID=22235899

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99932163A Withdrawn EP1121351A4 (fr) 1998-07-15 1999-07-01 Preparation d'ester methylique d'acide (s)-2-amino-6,6-dimethoxyhexanoique

Country Status (9)

Country Link
US (3) US6166227A (fr)
EP (1) EP1121351A4 (fr)
JP (1) JP2002520389A (fr)
KR (1) KR20010071895A (fr)
AU (1) AU753189B2 (fr)
CA (1) CA2337194A1 (fr)
HU (1) HUP0105151A3 (fr)
IL (1) IL140861A (fr)
WO (1) WO2000003981A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6162913A (en) * 1998-07-15 2000-12-19 Bristol-Myers Squibb Co. Preparation of [4S-(4α,7α,10aβ)]-4-amino-octahydro-5-oxo-7H-pyrido[2,1 -b] [1,3]thiazepine-7-carboxylic acid, methyl ester and salts thereof via novel disulfides
IL140861A (en) * 1998-07-15 2004-06-01 Bristol Myers Squibb Co Dioxolane pentanoic acid and processes for the preparation thereof
FR2813054B1 (fr) * 2000-08-21 2002-11-15 Faure Bertrand Equipements Sa Systeme pour vehicule, comportant un dispositif de commande adapte pour faire fonctionner un actionneur selectivement en fonction d'une valeur mesuree par un dispositif de mesure dispose dans un siege
US6620600B2 (en) * 2000-09-15 2003-09-16 Bristol-Myers Squibb Co. Enzymatic resolution of aryl and thio-substituted acids
DE10155065A1 (de) * 2001-11-09 2003-05-22 Degussa Verfahren zur Kristallisation von Oxonorleucinacetal

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EP0905257A1 (fr) * 1997-09-25 1999-03-31 Dsm N.V. Procédé de préparation de dérivés optiquement actifs d'acides 2-amino-omega-oxoalcanoiques

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EP0905257A1 (fr) * 1997-09-25 1999-03-31 Dsm N.V. Procédé de préparation de dérivés optiquement actifs d'acides 2-amino-omega-oxoalcanoiques

Also Published As

Publication number Publication date
JP2002520389A (ja) 2002-07-09
IL140861A (en) 2004-06-01
US6248882B1 (en) 2001-06-19
IL140861A0 (en) 2002-02-10
AU4852899A (en) 2000-02-07
KR20010071895A (ko) 2001-07-31
AU753189B2 (en) 2002-10-10
HUP0105151A2 (hu) 2002-04-29
EP1121351A2 (fr) 2001-08-08
CA2337194A1 (fr) 2000-01-27
US6329542B1 (en) 2001-12-11
WO2000003981A2 (fr) 2000-01-27
US6166227A (en) 2000-12-26
WO2000003981A8 (fr) 2001-06-28
WO2000003981A3 (fr) 2000-09-28
HUP0105151A3 (en) 2004-11-29

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